DESCRIPTION (Adapted from applicants' abstract) Dr. Laura Sterni, the PI, is an assistant professor who completed her pediatric pulmonary fellowship in 1996. In this application she outlines a program to study proposed mechanisms by which the carotid chemoreceptors increase their sensitivity in early postnatal life. The carotid chemoreceptors are oxygen sensors which are almost entirely responsible for driving the ventilatory response to hypoxia. Their sensitivity is weak at birth and requires the first few days to weeks of life to reset, increase their sensitivity to hypoxia, and assume the role of defending the infant from hypoxic stress. An understanding of the mechanisms involved in this postnatal resetting is likely to be important in understanding the pathogenesis of many disorders of neonatal respiratory control, including the Sudden Infant Death Syndrome (SIDS), the number one killer of infants over one month of age in the United States. The PI's fellowship project demonstrated that maturation of carotid chemoreceptor sensitivity to oxygen is due, at least in part, to changes within the chemosensory type I cell. These cells respond to stimuli with an increase in cytoplasmic calcium ([Ca2+]c) which then triggers neurotransmitter release. Type I cells isolated from mature animals had a significantly greater [Ca2+]c response to hypoxia and anoxia than cells isolated from newborns. These studies will investigate the role of intracellular Ca2+ stores in maturation of the [Ca2+]c response of type I cells to hypoxia. The hypotheses that will be tested are: (1) in the mature carotid chemoreceptor cell, intracellular Ca2+ stores modulate the rise in [Ca2+]c produced by voltage gated calcium entry; (2) the effect of the intracellular Ca2+ stores on the type I cell's hypoxia response changes during postnatal maturation; and (3) carotid chemoreceptor resetting is mediated partly by withdrawal of dopaminergic stimulation on Ca2+ influx and Ca2+ stores. The PI will take advantage of the strong mentoring, significant protected research time and the outstanding academic resources of the Johns Hopkins Medical Institutions to reach her goal of becoming an independent investigator in this important field.